Frontotemporal Dementia

Frontotemporal Dementia (FTD) is the second most common form of dementia after Alzheimer’s disease.

FTD is an age-related heterogeneous clinical syndrome characterized by early behavioral change and cognitive decline. It represents a group of primary degenerative dementias with predominant frontal and/or temporal lobe symptoms (e.g. decline in social and personal behavior, stereotyped behavior).  Approximately 10-20% of cases are genetically inherited (familial FTD) with the remaining 80% of cases occurring sporadically (sporadic FTD), with no known cause of disease.

Clinical Features

• Behavioral abnormalities
• Decreased initiative
• Social disinhibition
• Impulsivity, over-activity
• Emotional blunting
• Stereotyped behavior

Pathology of FTD

FTD disorders include frontotemporal lobar degeneration (also called dementia lacking distinctive histological features), frontotemporal lobar degeneration with motor neuron disease, corticobasal degeneration and FTD with parkinsonism linked to chromosome 17 (FTDP17). The neuropathological characteristics of FTD include frontal and temporal lobe atrophy with neuronal loss and gliosis (with tau or ubiquitinated inclusions). The microscopic pathology varies markedly in different forms of FTD.

Genetics of FTD

MAPT gene: Microtubule-associated protein tau, encoded by the MAPT gene is important for microtubule assembly and stabilization. About 50% of all autosomal dominant FTD families are explained by MAPT mutations. In the normal adult human brain, tau protein is soluble and exists as six isoforms. To date 42 pathogenic MAPT mutations have been reported in 124 families (age-at-onset 20-80 years). MAPT mutations are clustered in exons 9-13 and affect microtubule assembly or axonal transport. Some of the exon 10 missense substitutions and intronic mutations affect the splicing of exon 10 and cause an increase the 4-repeat tau isoform.

Progranulin (PGRN) gene

There are several dominant FTD families linked to the chromosome 17q21 region in which MAPT mutations were excluded. The disease in these families is caused by mutations in the progranulin gene (PGRN). To date 54 pathogenic PGRN mutations have been reported in 146 families. FTD is the result of the reduction of PGRN protein because the mutant form is destroyed. The PGRN gene encodes a secreted growth factor involved in the regulation of multiple processes including development, wound repair and inflammation. Patients with PGRN mutations do not have tau-pathology. Instead there are ubiquitin-immunoreactive neuronal cytoplasmic and intranuclear inclusions. A key component of these inclusions is Tar DNA-binding protein (TDP-43).

Chromatin-modifying protein 2B (CHMP2B) gene

CHMP2B mutation resulting in aberrant RNA splicing was reported to be the cause of autosomal dominant FTD in a large Danish family linked to chromosome 3p12.1. In addition, CHMP2B mutations were found in several patients with sporadic Amyotrophic lateral sclerosis (ALS). CHMP2B is expressed in neurons of most regions of the brain and its function is important for the recycling or degradation of cell surface receptors.